Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons Academic Article uri icon

Overview

MeSH Major

  • Alternative Splicing
  • Exons
  • Gene Expression Regulation, Enzymologic
  • Pyruvate Kinase

abstract

  • Alternative splicing of the pyruvate kinase M gene (PK-M) can generate the M2 isoform and promote aerobic glycolysis and tumor growth. However, the cancer-specific alternative splicing regulation of PK-M is not completely understood. Here, we demonstrate that PK-M is regulated by reciprocal effects on the mutually exclusive exons 9 and 10, such that exon 9 is repressed and exon 10 is activated in cancer cells. Strikingly, exonic, rather than intronic, cis-elements are key determinants of PK-M splicing isoform ratios. Using a systematic sub-exonic duplication approach, we identify a potent exonic splicing enhancer in exon 10, which differs from its homologous counterpart in exon 9 by only two nucleotides. We identify SRSF3 as one of the cognate factors, and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose metabolism. These findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect, and also have implications for other genes with a similar pattern of alternative splicing.

publication date

  • April 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3493165

Digital Object Identifier (DOI)

  • 10.1093/jmcb/mjr030

PubMed ID

  • 22044881

Additional Document Info

start page

  • 79

end page

  • 87

volume

  • 4

number

  • 2